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Abstract

With the discovery of the BRCA1 gene and other genetic mutations associated with breast
cancer, it has been established that hereditary mutations account for up to 5% of
patients presenting with breast cancer.

We performed a systematic review of English Language Literature to determine the role
of BRCA1 and BRCA2 gene mutations in African breast cancer patients. PUBMED and AJOL
database were searched for publications addressing Breast Cancer and BRCA1 and BRCA2
genes. PUBMED was searched using the following words in various combinations; ‘Breast
Cancer’, ‘BRCA1’, ‘BRCA2’, ‘BRCA’, ‘Genes’, ‘Cancer Genes’, and ‘Africa’.

16 studies fulfilled the study criteria up till December 2011. The studies were from
North Africa (NA) and Sub-Saharan Africa (SSA).

A total of 9 studies were found evaluating 752 (352 repeated Zhang J (2010)) patients
from SSA. Three studies (144 patients) evaluated all the coding regions of both BRCA1
and BRCA2 while 2 studies (571 patients) evaluated part(s) of BRCA1 and one (20 Patients)
evaluated part(s) of BRCA2, one re-evaluated the whole of the BRCA1 gene in a previous
sub-set of patients, while one (16 patients) evaluated parts of both BRCA1 and BRCA2.

In North Africa, 6 studies evaluated 374 patients, with 4 studies (219 patients) evaluating
the whole of the BRCA1 and BRCA2 genes while two (155 patients) studies evaluated
only parts of both BRCA1 and BRCA2, with one of the studies evaluating the whole of
the BRCA1 gene in a subset (24 patients).

Due to this paucity of well powered population based studies evaluating the influence
of BRCA genetic mutations in breast cancer patients in Africa, there is a need to
perform well powered studies and population screening to determine the impact of germ
line mutations in the Breast Cancer patient in Africa before any categorical statements
can be made with respect to their BRCA status.

Keywords:

Introduction

Epidemiology of breast cancer

Breast cancer is the most common malignancy affecting women worldwide. According to
GLOBOCAN there were 1.38 million new cases of breast cancer in the world in 2008,
with a corresponding mortality of 458,000. In Africa, over the same time period, there
were 68,000 new cases with 37,000 deaths documented, although this probably represents
a gross underestimation due to incomplete case ascertainment and reporting Adesunkanmi
et al. (2006). In 2010, the World Health Organisation (WHO) estimated that there would be 97,743
new breast cancer cases in Africa, with an estimated mortality of 52,855 IARC (2011).

The reportedly lower incidence of breast cancer in Africa may be explained by lower
life expectancy, incomplete record keeping and paucity of epidemiological studies
and incomplete case ascertainment. In addition, peculiarities in the presentation
of breast cancer in Africa may limit detection Adesunkanmi et al. (2006). These include an apparently younger age and later stage at presentation with more
aggressive tumour characteristics Adesunkanmi et al. (2006). The late presentation which may be a consequence of poor health seeking behaviour
is also compounded by the more aggressive nature of breast cancer in Africa.

The cause(s) of breast cancer remain largely unknown, though several risk factors
have been characterised. The most important factors are the age of the patient and
the effect of female sex hormones. Thus early menarche, late menopause and nulliparity
all confer an increased risk of breast cancer. Breast feeding is noted to be protective
while ingestion of exogenous female sex hormones is a risk factor for breast cancer.

A positive family history of breast cancer is known to increase the risk of breast
cancer. However, it was only in 1990, based on the results of linkage analysis performed
by Hall et al. (1990) that firm evidence was provided for the existence of at least one hereditary breast
cancer gene. Miki et al described the first germ line mutation known to confer increased
risk of breast cancer in 1994, labelled BRCA1 Miki et al. (1994). Shortly thereafter, a second germ line mutation associated with increased risk
was also identified and named BRCA2 Wooster et al. 1995). Subsequently, several susceptibility genes have been associated with breast cancer.
These genes confer ‘high-risk’ and ‘low to moderate risk’ of breast cancer. The high-risk
breast cancer susceptibility genes include BRCA1, BRCA2, PTEN, TP53, LKB1/STK11 and CDH1, with relative lifetime risks higher than 4 (but generally much higher at young ages).
The CHEK2, TGFβ1, CASP8 and ATM genes belong to the ‘low to moderate-risk’ breast cancer susceptibility genes Oldenburg
et al. (2007).

BRCA1 mutation carriers have a 30% risk of developing ovarian cancer during their
lifetime Whittemore et al. (1997) and a 50–80% risk of developing breast cancer before the age of 70 years Deng (2006). BRCA1 is mapped to chromosome 17q21 Adesunkanmi et al. (2006); it contains 24 exons and encodes a protein of 220 kDa, composed of 1863 amino acids
Chen et al. (1996). The second breast cancer susceptibility gene, BRCA2, is localized on the long arm
of chromosome 13. BRCA2 is also a large gene, with 27 exons that encode a protein
of 380 kDa, composed of 3418 amino acids Bertwistle et al. (1997).

Risk-associated truncation mutations are found throughout the entire BRCA1 coding
sequence Linger & Kruk (2010). The majority of risk-associated mutations are frameshift or nonsense mutations
that result in a premature stop codon and truncated protein product (NIH Breast Cancer
Information Core Database, http://research.nhgri.nih.gov/bic/webcite). Both BRCA1 and BRCA2 are thought to act as classical tumour suppressor genes and
the loss of their cellular functions is thought to occur through bi-allelic inactivation.
Carriers of mutations have one germline hit (the inherited mutated copy of BRCA1)
and, in the tumour, a second somatic hit usually through the loss of heterozygosity
Deng (2006; Collins et al. 1995).

A determination of BRCA genetic mutational status will go a long way towards advice
on prophylaxis for breast cancer. The data on BRCA gene mutations in Africans is sparse.
The mutational spectrum of BRCA1/2 in African Americans has not been as well characterized
as that of Caucasians Ferla et al. (2007).

The knowledge base about the various genetic mutations in the BRCA genes of people
of African origin is scattered in diverse small pockets of articles. The aim of this
study is to collate all these data and present them in a single review in order to
better characterise the genetic mutational spectrum of the indigenous African people.

Method

Data on breast cancer genetics in Africans was obtained via a literature search. The
key words were “Breast Cancer” and “Africa” with “Genes”, “BRCA Genes”, “BRCA1” and “BRCA2” in different combinations. The databases searched were PubMed, African Journals
Online (AJOL), the WHO HINARI database, and Ptolemy (University of Toronto library).
Only articles published in English were included. References of relevant articles
were also reviewed for additional literature. Studies combining and/or comparing Africans
with other ethnicgroups were included but only the data of the Africans analysed were
included in this review. Studies done outside Africa but which studied an indigenous
African people were included.

Result

BRCA1 and BRCA 2 mutations

Sub Saharan African (SSA)

In 1997, Stoppa-Lyonnet Stoppa-Lyonnet et al. (1997) evaluated the whole of the BRCA 1 gene and reported a case of frameshift truncating
BRCA1 mutation (926ins10) in a Breast Ovarian Cancer family from Ivory Coast.

Yawitch et al. (2000) evaluated 206 black South African women for 185delAG in exon 2, 4184del4, 943ins10
and 1832deI5 in exon 11, and 5382insC in exon 20, and Met1775Arg in exon 21 mutations
in BRCA1. Eleven of these patients had a family history of Breast cancer. None of
these mutations were found in any of the patients studied.

Gao Q et al. (2000) screened 70 young African breast cancer patients with early onset breast cancer
in Ibadan, Nigeria. Only one of the patients had a family history of breast cancer.
All the regions of the BRCA1 and BRCA2 genes were analysed. Eighteen (23%) of the
patients had mutations. Three truncating mutations (2 BRCA1 and 1 BRCA2) were detected.
Twenty four non truncating mutations (4 BRCA1 and 20 BRCA2) were also detected in
this cohort.

40 years) patients in Nigeria. Twenty nine (74%) patients carried a genetic variation
in BRCA1 (4 variants), BRCA2 (30 variants) or both genes. However, they found only
1 (3034del4) truncating mutation located on exon 11 of BRCA2. The rest were either
unclassified variants or polymorphisms. They went further to test the clinical significance
of their finding by examining the BRCA genes of 74 unaffected Nigerians. Five of 13
BRCA2 variations expected to result in deleterious amino acid substitutions were not
found in the controls.

A truncating mutation in BRCA1 (Y101X (422 T > G), exon 7) previously identified in
Nigerian Breast Cancer patients led Zhang et al. (2009) to screen 365 Nigerian women with Breast cancer and 177 controls for this mutation.
This genetic mutation was further discovered in 3 other unrelated patients. All the
patients were of the Yoruba ethnic group.

Masri et al. (2002) studied 20 unselected breast cancer patients in Sudan. They analysed Exon 11 of
the BRCA2 gene and exon 5–9 of the p53 codon. Four of the patients had a family history
of Breast carcinoma, while 1 of the patients – with a family history – had bilateral
disease. They found only 1 somatic mutation and 1 polymorphism. They however did not
elaborate on the type of mutation and/or the base pairs involved.

40 years) and 1 Male Breast Cancer patient in central Sudan. All the coding regions
of BRCA1 and BRCA2 were analysed. Majority of the patients (33/35) had mutations.
They found 5 truncating mutations (2 in BRCA1, 3 in BRCA2) in 5 patients, one of which,
(BRCA2) was in the male patient. They also found 55 unclassified variants (30 in BRCA1,
25 in BRCA2), 5 of which were predicted to affect protein function.

Zhang et al. (2010) evaluated 352 patients from Nigeria previously determined not to have any germline
mutations for either BRCA1 or BRCA2 for large genomic rearrangement (LGR). Multiplex
ligation-dependent probe amplification (MLPA) was used to screen BRCA1 rearrangements
in these patients. They found only 1 patient with a deletion of exon 21.

van der Merwe et al. (2010) screened 16 Black Xhosa patients with breast cancer referred for genetic testing
for 6 founder mutations (3 Ashkenazi and 3 Afrikaner). None of these patients carried
any of these common founder mutations. They found a mutation on exon 11 of the BRCA2
gene. They then went ahead to screen exon 10 of BRCA1 and exon 10 & 11 of BRCA2. Four
of the Xhosa women were found to have a BRCA2 mutation on exon 11. This mutation was
also found to be present in 4 out of 105 Colored patients referred for genetic testing.

North African (NA)

Balci et al. (1999) evaluated BRCA1 and BRCA2 in Turkish breast and ovarian cancer patients with a strong
family history of breast cancer in 1999. The whole of the genes were evaluated. In
this group of 15 Families of 33 patients, three deleterious mutations (2 BRCA1 and
1 BRCA2) were detected. The BRCA2 mutation was detected in one of the male breast
cancer patients.

Ozdag et al. (2000) in 2000 published a study on 50 high risk Turkish Breast cancer patients. Patients
were selected based on four criteria; early age at onset, male breast cancer, hereditary
breast cancer and familial breast cancer. Exons 2, 5, 11 (10 overlapping fragments),
13, 20 & 24 of BRCA1, and exon 11 (7 overlapping fragments) of BRCA2 were analysed.
Four deleterious mutations were found. There were 2 (BRCA2) mutations in the patients
with hereditary breast cancer. The other 2 (BRCA1) mutations were found in patients
with early onset breast cancer. One of these patients had 2 mutant alleles. There
was no truncating mutation discovered in the male breast cancer group. There were
5 BRCA1 sequence variants detected in 23 other patients.

In another Turkish study, Yazici et al. (2000) found 8 BRCA1 and 2 BRCA2 mutations in 11 out of a cohort of 105 patients with breast
or ovarian cancer. One (1) of the mutations was found only in an ovarian cancer patient
and will not be part of the summary. Half of the patients had a family history while
the remaining half had early onset breast cancer (

<

50 years). Their analysis was initially limited to exon 11 of both genes and exon
10 of BRCA2. They also performed complete analysis of the BRCA1 gene in a subset of
24 patients and found further mutations in exons 14 and 20, one of which was the Askenazi
Jewish mutation 5382insC. This led them to do a heteroduplex analysis of exons 2,
14 and 20 of the BRCA1 gene in all the patients. There was a higher incidence of BRCA
mutations (7 BRCA1 and 1 BRCA2) in patients with a family history. Five truncating
mutations were identified in exon 11 of both genes. The remaining mutations were in
exon 2, 14, 20 and intron 14.

Uhrhammer et al. (2008) performed a study to determine the contribution of BRCA1 mutations to breast cancer
in Algeria. The patient population (64) was selected on account of a family history
of Breast cancer (13) and early onset Breast cancer (51) (

<

38 yrs). They evaluated the whole of the BRCA1 gene. A total of 7 deleterious mutations
were found in 11 patients representing 9 families. One of these mutations was found
in a patient with early onset breast cancer and another patient with familial breast
cancer. Another mutation was found in 2 different families with familial breast cancer.

Troudi et al. (2007) in Tunisia studied 36 patients with family history of breast or ovarian cancer.
All of the BRCA1 and BRCA2 genes were analyzed. They found 6 deleterious mutations
in 7 patients. Four of these were in BRCA1 (5 patients) and the remainder were in
BRCA2 (2 patients). In addition to these mutations, nine distinct unclassified sequence
variants (8 in BRCA1 and 1 in BRCA2) and 16 distinct polymorphisms (12 in BRCA1 and
4 in BRCA2) were identified.

Cherbal et al. (2010) studied 86 high risk individuals – male breast cancer, strong family history of
breast, ovarian and/or prostate cancers – from 70 families. All the regions of the
BRCA1 and BRCA2 genes were evaluated for mutations. Individuals were screened by High-Resolution
Melting (HRM) curve analysis followed by direct sequencing. Samples for which no pathogenic
mutation was found were analyzed by MLPA. Three pathogenic mutations in BRCA1 gene and two within BRCA2 gene were detected using PCR and HRM. Using MLPA, a novel deletion of BRCA1 exon 2 and a deletion of BRCA1 exon 8 were identified in two patients with breast/ovarian cancer and bilateral breast
cancer, respectively. The mutations occurred in 8 of 70 families.

Mahfoudh et al. (2011) studied 24 patients in 16 breast/ovarian cancer families. All the coding regions
of the BRCA1 gene were analysed. Six families had four deleterious mutations one of
which (IVS5 + 2insG) was novel. Another of the mutations (916delTT) was noted in 3
apparently unrelated families.

Tables 1, 2, 3 show a summary of the studies, the portion(s) of the gene(s) evaluated in each study
and the mutation(s) detected.

Discussion

Throughout the continent of Africa, over a seventeen year period, 16 studies have
evaluated 1150 patients for mutations in the BRCA1 and/or BRCA2 genes in breast cancer
patients. Seven hundred and fifty two from SSA and 398 from NA. Four studies evaluated
parts of BRCA1 & 2 in 171 patients, 5 studies evaluated the whole of the BRCA1 gene
in 465 patients, 6 studies evaluated all the regions of both genes in 299, while 2
studies evaluated parts of BRCA1 in 571 and 1 study evaluated part of BRCA2 in 20
patients.

In this period, the evaluation of genetic mutations in African breast cancer patients
has improved from the anecdotal reports of Stoppa-Lyonnet and the evaluation of specific
mutations by Yawitch to the discovery of LGRs by Zhang.

In the African breast cancer patients studied, LGRs were found rarely. In some areas,
LGRs were also rare in breast and ovarian cancer families de la Hoya et al. (2006; Engert et al. 2008). This contrasts with other areas of the world where Genomic rearrangements account
for more than one-third of the brca1 mutations in northern Italian breast/ovarian
cancer families Montagna et al. (2003).

Conclusion

In spite of the lower age at presentation and more aggressive nature of breast cancer
in African patients and the association of genetic mutations with breast cancer in
young women, there has been a paucity of studies evaluating the genetic basis of breast
cancer in this patient population. Evaluation of only 1,150 patients in a disease
with a 5 year prevalence of 302,310 at a rate of less than one (1) study per year
since the discovery of the BRCA gene is less than adequate. Most of the studies did
not evaluate all the coding regions of the genes. Some of them only examined either
BRCA1 or BRCA2. Some mutations were found and documented. However, the clinical significance
of some of the germ line mutations identified and the clinical application is yet
to be confirmed. This is because these studies were grossly underpowered to make any
far reaching conclusion about the genetics of the African patient with Breast Cancer.
There is therefore a need to perform well powered studies and population screening
to determine the impact of germ line mutations in the African Breast Cancer patient.